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La investigación se centra en analizar el impacto de la contaminación por nitrato en las masas de aguas subterráneas de la Demarcación Hidrológica del Segura bajo un enfoque fuente-vía-receptor y su particular incidencia en el área de captación de la laguna litoral del Mar Menor, con los siguientes objetivos específicos: (1) valorar la eficacia de las zonas vulnerables a la contaminación por nitrato (ZVNs) mediante el análisis estadístico de los niveles de contaminación en sus masas de agua subterránea durante el periodo 2010-2021; (2) analizar la distribución actual del nitrato en las masas de agua subterránea para identificar las zonas contaminadas y en riesgo; (3) delimitar y caracterizar las áreas de captación de las zonas afectadas por la contaminación; y (4) explorar el papel del medio físico y de los usos del suelo en la distribución de las zonas contaminadas por nitrato mediante el análisis de componentes principales (ACP) de sus áreas de captación. Dado el grave estado de degradación ambiental del Mar Menor, se analiza con especial atención la incidencia de la contaminación por nitrato en las aguas subterráneas (receptoras primarias) que drenan a la laguna (receptora secundaria) y se identifican los territorios que conforman su área de captación. No se han observado diferencias interanuales estadísticamente significativas en los niveles de nitrato de las masas de agua subterránea afectadas por contaminación de nitrato durante el periodo 2010-2021, lo que sugiere que las ZVNs designadas en la Demarcación del Segura no parecen estar cumpliendo, por el momento, con las expectativas de reducir la contaminación. Utilizando el área de captación de las zonas contaminadas como unidad de análisis, el ACP evidenció la relación directa entre la extensión de las superficies contaminadas y la agricultura intensiva de cultivos de herbáceos en regadío, cítricos y frutales (grupos de cultivos que presentan los mayores excedentes anuales de N de la Demarcación). En contraposición, las áreas de montaña, con abundancia de bosques y escasa presencia agrícola, constituyen un claro elemento protector para los recursos hídricos frente a los procesos de contaminación por el nitrato procedente de fuentes difusas. La situación de emergencia ecológica del Mar Menor es consecuencia de su grave estado de eutrofización, al que contribuye el sobreexceso de N procedente de descargas subterráneas ricas en nitrato desde el acuífero Cuaternario de la masa de agua Campo de Cartagena. A la vista de los resultados y como paso previo al reforzamiento de los programas de acción de las ZVNs de la Demarcación del Segura, se propone analizar la idoneidad de las 89 ZVNs designadas en la Demarcación mediante validaciones frente a un mapa de vulnerabilidad específica a la contaminación por nitrato y revisarlas si procede.

Abstract Objective As of 2022, 36 anti‐seizure medications (ASMs) have been licensed for the treatment of epilepsy, however, adverse effects (AEs) are commonly reported. Therefore, ASMs with a wide margin between therapeutic effects and AEs are preferred over ASMs that are associated with a narrow margin between efficacy and risk of AEs. E2730 was discovered using in vivo phenotypic screening and characterized as an uncompetitive, yet selective, inhibitor of γ‐aminobutyric acid (GABA) transporter 1 (GAT1). Here, we describe the preclinical characteristics of E2730. Methods Anti‐seizure effects of E2730 were evaluated in several animal models of epilepsy: corneal kindling, 6 Hz–44 mA psychomotor seizure, amygdala kindling, Fragile X syndrome, and Dravet syndrome models. Effects of E2730 on motor coordination were assessed in accelerating rotarod tests. The mechanism of action of E2730 was explored by [3H]E2730 binding assay. The GAT1‐selectivity over other GABA transporters was examined by GABA uptake assay of GAT1, GAT2, GAT3, or betaine/GABA transporter 1 (BGT‐1) stably expressing HEK293 cells. To further investigate the mechanism for E2730‐mediated inhibition of GAT1, in vivo microdialysis and in vitro GABA uptake assays were conducted under conditions of different GABA concentrations. Results E2730 showed anti‐seizure effects in the assessed animal models with an approximately >20‐‍fold margin between efficacy and motor incoordination. [3H]E2730 binding on brain synaptosomal membrane was abolished in GAT1‐deficient mice, and E2730 selectively inhibited GAT1‐mediated GABA uptake over other GABA transporters. In addition, results of GABA uptake assays showed that E2730‐mediated inhibition of GAT1 positively correlated to the level of ambient GABA in vitro. E2730 also increased extracellular GABA concentration in hyperactivated conditions but not under basal levels in vivo. Significance E2730 is a novel, selective, uncompetitive GAT1 inhibitor, which acts selectively under the condition of increasing synaptic activity, contributing to a wide margin between therapeutic effect and motor incoordination.

Early-life seizures (ELSs) can cause permanent cognitive deficits and network hyperexcitability, but it is unclear whether ELSs induce persistent changes in specific neuronal populations and whether these changes can be targeted to mitigate network dysfunction. We used the targeted recombination of activated populations (TRAP) approach to genetically label neurons activated by kainate-induced ELSs in immature mice. The ELS-TRAPed neurons were mainly found in hippocampal CA1, remained uniquely susceptible to reactivation by later-life seizures, and displayed sustained enhancement in [alpha]-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated (AMPAR-mediated) excitatory synaptic transmission and inward rectification. ELS-TRAPed neurons, but not non-TRAPed surrounding neurons, exhibited enduring decreases in Gria2 mRNA, responsible for encoding the GluA2 subunit of the AMPARs. This was paralleled by decreased synaptic GluA2 protein expression and heightened phosphorylated GluA2 at Ser880 in dendrites, indicative of GluA2 internalization. Consistent with increased GluA2-lacking AMPARs, ELS-TRAPed neurons showed premature silent synapse depletion, impaired long-term potentiation, and impaired long-term depression. In vivo postseizure treatment with IEM-1460, an inhibitor of GluA2-lacking AMPARs, markedly mitigated ELS-induced changes in TRAPed neurons. These findings show that enduring modifications of AMPARs occur in a subpopulation of ELS- activated neurons, contributing to synaptic dysplasticity and network hyperexcitability, but are reversible with early IEM- 1460 intervention., Introduction Both clinical and experimental evidence suggest that seizures in early life can be associated with long-lasting cognitive and behavioral deficits (1-6), yet the mechanisms of these long-term changes remain [...]

Cardiovascular disease (CVD) is the primary cause of death and disability worldwide. Although age-standardized CVD mortality rates decreased globally by 14.5% between 2006 and 2016, the burden of CVD remains disproportionately higher in low- and middle-income countries compared to high-income countries. Even though proven, effective approaches based on multiple-drug intake aimed at the prevention and treatment of CVD are currently available, poor adherence, early discontinuation of treatment, and suboptimal daily execution of the prescribed therapeutic regimes give rise to shortfalls in drug exposure, leading to high variability in the responses to the prescribed medications. Wald and Law, in their landmark paper published in BMJ 2003, hypothesized that the use of a fixed-dose combination of statins, β-blockers, angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and aspirin (classic Polypill composition) may increase adherence and decrease CVD by up to 80% when prescribed as primary prevention or in substitution of traditional protocols. Since then, many clinical trials have tested this hypothesis, with comparable results. This review aims to describe the available clinical trials performed to assess the impact of fixed-dose combinations on adherence, cost-effectiveness, and the risk factors critical to the onset of CVD.

Smart polymeric micelles (PMs) are of great interest in drug delivery owing to their low critical micellar concentration and sizes. In the present study, two different pH-sensitive poly(2-vinyl pyridine)-b-poly(ethylene oxide) (P2VP-b-PEO) copolymer samples were used for the encapsulation of paclitaxel (PTX), ursolic acid (UA), and dual loading of PTX and UA. Based on the molecular features of copolymers, spherical PMs with sizes of around 35 nm and 140 nm were obtained by dialysis for P2VP55-b-PEO284 and P2VP274-b-PEO1406 samples, respectively. The micellar sizes increased after loading of both drugs. Moreover, drug encapsulation and loading efficiencies varied from 53 to 94% and from 3.2 to 18.7% as a function of the copolymer/drug ratio, molar mass of copolymer sample, and drug type. By FT-IR spectroscopy, it was possible to demonstrate the drug loading and the presence of some interactions between the polymer matrix and loaded drugs. In vitro viability was studied on 4T1 mammary carcinoma mouse cells as a function of time and concentration of drug-loaded PMs. UA-PMs and free PMs alone were not effective in inhibiting the tumor cell growth whereas a viability of 40% was determined for cells treated with both PTX- and PTX/UA-loaded PMs. A synergic effect was noticed for PTX/UA-loaded PMs.

A variety of cat breeds have been developed via novelty selection on aesthetic, dermatological traits, such as coat colors and fur types. A recently developed breed, the lykoi (a.k.a. werewolf cat), was bred from cats with a sparse hair coat with roaning, implying full color and all white hairs. The lykoi phenotype is a form of hypotrichia, presenting as a significant reduction in the average numbers of follicles per hair follicle group as compared to domestic shorthair cats, a mild to severe perifollicular to mural lymphocytic infiltration in 77% of observed hair follicle groups, and the follicles are often miniaturized, dilated, and dysplastic. Whole genome sequencing was conducted on a single lykoi cat that was a cross between two independently ascertained lineages. Comparison to the 99 Lives dataset of 194 non-lykoi cats suggested two variants in the cat homolog for Hairless (HR) (HR lysine demethylase and nuclear receptor corepressor) as candidate causal gene variants. The lykoi cat was a compound heterozygote for two loss of function variants in HR, an exon 3 c.1255_1256dupGT (chrB1:36040783), which should produce a stop codon at amino acid 420 (p.Gln420Serfs*100) and, an exon 18 c.3389insGACA (chrB1:36051555), which should produce a stop codon at amino acid position 1130 (p.Ser1130Argfs*29). Ascertainment of 14 additional cats from founder lineages from Canada, France and different areas of the USA identified four additional loss of function HR variants likely causing the highly similar phenotypic hair coat across the diverse cats. The novel variants in HR for cat hypotrichia can now be established between minor differences in the phenotypic presentations.

Cancers require telomere maintenance mechanisms for unlimited replicative potential. They achieve this through TERT activation or alternative telomere lengthening associated with ATRX or DAXX loss. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, we dissect whole-genome sequencing data of over 2500 matched tumor-control samples from 36 different tumor types aggregated within the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium to characterize the genomic footprints of these mechanisms. While the telomere content of tumors with ATRX or DAXX mutations (ATRX/DAXXtrunc) is increased, tumors with TERT modifications show a moderate decrease of telomere content. One quarter of all tumor samples contain somatic integrations of telomeric sequences into non-telomeric DNA. This fraction is increased to 80% prevalence in ATRX/DAXXtrunc tumors, which carry an aberrant telomere variant repeat (TVR) distribution as another genomic marker. The latter feature includes enrichment or depletion of the previously undescribed singleton TVRs TTCGGG and TTTGGG, respectively. Our systematic analysis provides new insight into the recurrent genomic alterations associated with telomere maintenance mechanisms in cancer.

One of the most frequent types of dementia is the Alzheimer’s disease (AD). The fundamental concepts of pharmacotherapy valid for AD are substances that increase the cerebral acetylcholine level, intervening in cholinergic neurotransmission through cholinesterase inhibition and N-methyl D-aspartate receptor antagonists. These drugs have the role of slowing down the further evolution of the disease, providing at the same time a symptomatic improvement. The effectiveness of these drugs is clearly limited, both because of several negative side effects and their inefficiency to cure the disease. The therapeutic management is therefore a major challenge in AD, and the non-adherence to treatment often constitutes a serious barrier to an effective therapy. Doctors and pharmacists play a vital role in the pharmacotherapeutic management of AD, contributing to improved clinical results and quality of life of the patient. The current review analysed the challenges in therapeutic management, especially those related to treatment adherence and pharmacist involvement.

Introduction. Probiotics are well-known adjuvants, used as complementary therapeutic agents in health (e.g. gastrointestinal or metabolic) disorders, considering their beneficial role on gut microbiota, and their support in immunity. The objective of the study was to evaluate the impact of probiotic supplementation on abundance of Bacteroides spp. in intestinal microbiome of patients with Crohn’s disease (CD). Materials and methods. The comparative evaluation was conducted over a 6-month period, on 49 subjects diagnosed with CD, who were separated into two groups, as follows: the study group (probiotics associated with allopathic treatment) and the control group (only allopathic treatment). All patients were evaluated at baseline and at 6 months. Demographic characteristics, associated pathology, and the evolution of intestinal microbiome and faecal pH were followed. Results. In this research, the microbiome of patients with CD showed changes in the abundance of bacterial species. The combination of probiotic treatment led to the following changes: Escherichia coli ​(from 5.77×107 to 4.15×107, p=0.006) and Enterobacter spp. ​(from 1.92×104 to 1.17×104, p=0.009) values decreased significantly and Faecalibacterium prausnitzii (from 3.73×108 to 4.55×108, p=0.003), Bifidobacterium spp. (from 4.76×106 to 4.92×106, p

Legumes are essential plants in dryland ecosystems worldwide because they increase nitrogen availability, so their understanding is vital for improving knowledge and modelling in the face of climate change.This work studies the differences in resource use efficiency and their relationship with photosynthetic, photochemical, bioelemental, and stoichiometric traits of coexistent legumes and non‐legumes in a Sonoran Desert ecosystem.We found that legumes had higher photosynthetic rates, intrinsic and seasonal water use efficiency (WUE), phosphorus use efficiency (PPUE), and higher light utilisation mediated by chlorophyll content and active reaction centers, which may increase their photoprotection. Legumes can increase their WUE and PPUE with no changes in nitrogen use efficiency (PNUE). Consequently, observed trait relationships between studied traits in these legumes have significant differences with the non‐legume species in the study.Stoichiometry is helpful, in some cases, as an indicator of nutrient use efficiency and enables functional group differentiation.Our results strongly relate legumes' higher resource use efficiency with their success in dryland ecosystems. Read the free Plain Language Summary for this article on the Journal blog. [ABSTRACT FROM AUTHOR]

The four-decade evolution of drinking water policy of the European Union is analysed using a policy change framework through documentary analysis and in-depth interviews. Our findings suggest that this policy has always targeted the protection of human health while inching closer to the concept of 'safely managed drinking water', which implies the protection of the sources of drinking water and the application of a risk-based approach to the entire water supply chain. Influenced by a variety of factors, it has experienced incremental changes leading to more comprehensive provisions while seeking flexibility to accommodate the diversity of Member States forming the Union. [ABSTRACT FROM AUTHOR]

La yerba mate (Ilex paraguariensis A. St. -Hil.) es un cultivo primario y de gran importancia para el noreste de Argentina. En los últimos años, la enfermedad conocida como “mal de la tela”, cuyo agente causal es Ceratobasidium niltonsouzanum, está ocasionando importantes daños en la producción; y debido a la poca información existente su manejo resulta muy difícil.Al inicio de la enfermedad los signos incluyen cordones de micelios blancos visibles sobre las ramas y hojas infectadas. Las hojas se necrosan, se secan y quedan colgando de las ramas por la hifa del hongo. A partir de hojas y ramas sintomáticas, muestreadas de distintas partes de la provincia de Misiones, fue aislado el agente causal para su posterior caracterización morfológica y molecular. Las colonias fueron aisladas y crecieron rápidamente sobre medios de APG (agar papa glucosado), presentando un color blanquecino al inicio, tornándose luego de un color castaño. Con la caracterización morfológica se pudo determinar que el hongo se encuentra distribuido en distintas partes de la provincia de Misiones, afectando las plantaciones con distintos niveles de incidencia. Pruebas de patogenicidad, conducidas en laboratorio, permitieron conocer el progreso de la enfermedad bajo condiciones ambientales favorables. El objetivo del presente trabajo fue contribuir al conocimiento de la enfermedad, con la descripción de síntomas y signos, condiciones predisponentes y caracteres morfológicos y moleculares del agente causal del “mal de la tela”.

Introduction. The composition of gut microbiota can be affected by type 2 diabetes mellitus (T2DM) and metabolic syndrome (MS), its improvement is frequently ignored in metabolic disorders. The objective of the study was a comparative evaluation of the faecal microbiota of healthy controls and of T2DM and MS patients (n = 150). Materials and methods. A retrospective cross-sectional study was performed, between July 2019-December 2020 in the Bio-standard laboratory Oradea, Romania. A group of 75 patients with non-insulin dependent T2DM and MS (study group = SG) and 75 healthy subjects (control group = CG) has been included in the study. The composition of the microbiome and the influence of oral antidiabetic treatment on the microbiome in SG patients were compared. Results. 8 out of 19 species of the analysed bacteria had a different relative abundance in the SG, compared to CG; Enterococcus spp. were significantly higher (3.18×106 vs 1.94×106, p=0.004), while Akkermansia muciniphila (2.55×109 vs. 4.66×109, p

Introduction. Probiotics are well-known adjuvants, used as complementary therapeutic agents in health (e.g. metabolic or gastrointestinal) disorders, considering their beneficial role on gut microbiota, and their support in immunity. The objective of the study. This research followed the impact of probiotic supplementation on some clinical parameters related to metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM) (weight status, body mass index, carbohydrate/ lipid profiles). Materials and methods. The comparative monitoring of the parameters was conducted over a 3- month period, on 41 subjects diagnosed with both MS and T2DM, who were separated into two groups, as follows: the study group (probiotics associated with allopathic treatment) and the control group (without probiotics). Results. Administration of dietary probiotics had a major impact on body weight, weight loss being significantly enhanced in the probiotic group than in the diet-only group (p=0.01). The effect of dietary probiotic administration on glucidic and lipidic profile was small (effect size (ES) 0.26 and 0.33, respectively), but better than in the control group, in whom the evolution was insignificant (ES 0.10 and 0.10, respectively). From a statistical point of view, the differences were insignificant (p>0.05). Conclusions. In the metabolic profile management of patients suffering from both MS and T2DM, probiotics administration had beneficial results, as highlighted by the results of the present study.

Androgen insensitivity syndrome (AIS) is an X-linked recessive genetic syndrome that occurs as result of an androgen receptor mutation; it affects the normal masculinization process in chromosomal male patients. More than 900 androgen receptor mutations that can lead to AIS have been identified. The complete androgen insensitivity is characterized by a total lack of response to androgens, usually in patients with 46XY karyotype but with feminine phenotype. Primary amenorrhoea and inguinal swellings in female patients are the main signs that could raise suspicion for this syndrome. Patients with partial androgen insensitivity have ambiguous genitalia at birth and gynecomastia during puberty, whereas those with mild androgen insensitivity present a normal male phenotype but altered spermatogenesis during adulthood and pubertal gynecomastia. The diagnosis of AIS often proves to be a challenge; its management is complex and requires a multidisciplinary approach to meet decision-making challenges in sex assignment, fertility and timing of gonadectomy, psychological outcomes and genetic counselling.

The transition to college includes exposure to new cultures, such as the college drinking culture, which is likely to be encountered within the first few weeks. We conducted a qualitative content analysis of 242 first-semester undergraduate students' written comments to open-ended questions about their perceptions of and expectations for involvement in the college drinking culture. Four groups emerged from our analyses: Non-Endorsers, Autonomous Drinkers, Have Bought In, and Law Abiders. A greater proportion of men than women were in the Have Bought In group. Groups were found to vary in their self-reported binge-drinking experiences, which was greater for the Have Bought In group compared to all other groups. In addition, the Autonomous Drinkers group had more binge-drinking experiences than the Non-Endorsers and Law Abiders groups. Findings are discussed in terms of implications for alcohol-related intervention for transitioning students.

Cyclin‐dependent kinase‐like 5 (CDKL5) deficiency disorder (CDD) is caused by a loss‐of‐function mutation in CDKL5 gene, encoding a serine–threonine kinase highly expressed in the brain. CDD manifests with early‐onset epilepsy, autism, motor impairment and severe intellectual disability. While there are no known treatments for CDD, the use of cannabidiol has recently been introduced into clinical practice for neurodevelopmental disorders. Given the increased clinical utilization of cannabidiol, we examined its efficacy in the CDKL5R59X knock‐in (R59X) mice, a CDD model based on a human mutation that exhibits both lifelong seizure susceptibility and behavioural deficits. We found that cannabidiol pre‐treatment rescued the increased seizure susceptibility in response to the chemoconvulsant pentylenetetrazol (PTZ), attenuated working memory and long‐term memory impairments, and rescued social deficits in adult R59X mice. To elucidate a potential mechanism, we compared the developmental hippocampal and cortical expression of common endocannabinoid (eCB) targets in R59X mice and their wild‐type littermates, including cannabinoid type 1 receptor (CB1R), transient receptor potential vanilloid type 1 (TRPV1) and 2 (TRPV2), G‐coupled protein receptor 55 (GPR55) and adenosine receptor 1 (A1R). Many of these eCB targets were developmentally regulated in both R59X and wild‐type mice. In addition, adult R59X mice demonstrated significantly decreased expression of CB1R and TRPV1 in the hippocampus, and TRPV2 in the cortex, while TRPV1 was increased in the cortex. These findings support the potential for dysregulation of eCB signalling as a plausible mechanism and therapeutic target in CDD, given the efficacy of cannabidiol to attenuate hyperexcitability and behavioural deficits in this disorder. [ABSTRACT FROM AUTHOR]

Background: Typical absence seizures (AS) are epileptic phenomena typically appearing in children 4–15 years of age and can be elicited by hyperventilation (HV). Hyperventilation-induced high-amplitude rhythmic slowing (HIHARS) represents a paraphysiological response during HV and may manifest with alteration of awareness (HIHARSAA). To date, HIHARSAA has mostly been described in patients without epilepsy. Aim: To describe five patients with treatment-responsive typical AS who, after becoming seizure free, presented with HIHARSAA. Methods: By using video-electroencephalographic recording (Video-EEG), we describe differential clinical characteristics and ictal electrophysiological patterns of both typical AS and HIHARSAA. Results: We demonstrate that when HIHARSAA occurs in patients with typical AS there is a temporal window between the two phenomena. This suggests that the presence of typical AS precludes the appearance of HIHARSAA. Conclusions: We hypothesize that alkalosis and dysfunction of the same neural network are involved in both typical AS and HIHARSAA and that their distinct electroclinic manifestations are due to the involvement of different ion channels. Significance: A better understanding of the characteristics of typical AS and HIHARSAA and of the role of alkalosis in both, can help avoiding misdiagnosis and identifying more suitable therapies for typical AS.